Human oncoprotein Musashi-2 N-terminal RNA recognition motif backbone assignment and identification of RNA-binding pocket.
Human oncoprotein Musashi-2 N-terminal RNA recognition motif backbone assignment and identification of RNA-binding pocket.
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DOI：
10.18632/oncotarget.22540
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发表时间：
2017-12-05
期刊：
影响因子：
--
通讯作者：
Xu L
中科院分区：
文献类型：
--
作者：
Lan L;Xing M;Douglas JT;Gao P;Hanzlik RP;Xu L
RNA结合蛋白Musashi-2(MSI2)是干细胞中的关键调节因子，在多种肿瘤中过度表达，其高表达与预后不良有关。与Musashi-1一样，它含有两个N末端RRMS(RNA识别基序，也称为RNA结合域)，RRM1和RRM2，它们介导与目标mRNAs的结合。以前的研究已经获得了Musashi-1的rbds和Rbd1：RNA复合体的三维结构。在此，我们在荧光偏振分析和时间分辨荧光共振能量转移分析中显示了MSI2-RRM1与15nT数量RNA结合。利用核磁共振波谱归属了MSI2-RRM1的主链共振，并表征了RRM1与Numb RNA r(GUAGU)的直接相互作用。我们的核磁共振滴定和结构模拟研究表明，MSI2-RRM1和MSI1-Rbd1具有相似的RNA结合事件和结合口袋。这项工作为MSI2-RRM1的结构和RNA结合口袋提供了重要的信息，为MSI2特异性和MSI1/MSI2双重抑制剂的开发做出了贡献。
RNA-binding protein Musashi-2 (MSI2) is a key regulator in stem cells, it is over-expressed in a variety of cancers and its higher expression is associated with poor prognosis. Like Musashi-1, it contains two N-terminal RRMs (RNA-recognition Motifs, also called RBDs (RNA-binding Domains)), RRM1 and RRM2, which mediate the binding to their target mRNAs. Previous studies have obtained the three-dimensional structures of the RBDs of Musashi-1 and the RBD1:RNA complex. Here we show the binding of MSI2-RRM1 to a 15nt Numb RNA in Fluorescence Polarization assay and time resolved Fluorescence Resonance Energy Transfer assay. Using nuclear magnetic resonance (NMR) spectroscopy we assigned the backbone resonances of MSI2-RRM1, and characterized the direct interaction of RRM1 to Numb RNA r(GUAGU). Our NMR titration and structure modeling studies showed that MSI2-RRM1 and MSI1-RBD1 have similar RNA binding events and binding pockets. This work adds significant information to MSI2-RRM1 structure and RNA binding pocket, and contributes to the development of MSI2 specific and MSI1/MSI2 dual inhibitors.
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